Thrombotic cardiovascular diseases including venous thromboembolism, myocardial infarction, and ischemic stroke, remain leading causes of death and disability in the US. Although effective antithrombotic agents are available, these drugs inadvertently target vital hemostatic molecular mechanisms and can produce severe dose-limiting hemorrhagic toxicity, thereby limiting their use. Consequently, there is a significant and urgent unmet medical need for safe antithrombotic treatment alternatives. The proposed research will determine whether monoclonal antibodies against coagulation factor XI (AXIMABs) hold promise for the safe prevention and treatment of acute thrombosis. Initially we will study the unique proprietary antibody 14E11, which targets the apple 2 domain of coagulation factor XI (FXI) and prevents its activation by factor XIIa (FXIIa). To justify eventual clinical development and commercialization, we will first establish in primates the hemostatic safety and antithrombotic efficacy of 14E11 compared with the market leader for relevant indications, low-molecular- weight heparin (enoxaparin). The proposed research has three specific aims. Aim 1: to prepare and characterize neutralizing 14E11 for preclinical product candidate evaluation. The quantitative milestone for Aim 1 is to establish the minimum saturating dose of 14E11 that produces effective anticoagulation for at least 24 hours in baboons. Aim 2: to determine the efficacy of 14E11 compared with enoxaparin in a baboon venous thrombosis model. The quantitative milestone for Aim 2 is to document a significant antithrombotic effect of 14E11, at a saturating dose, that is comparable to that achieved by a clinically relevant dose of enoxaparin. Aim 3: to determine the hemostatic safety of 14E11 in aspirin-treated baboons. The quantitative milestone for Aim 3 is to demonstrate that 14E11 produces significantly less hemostatic impairment (bleeding) versus that seen in enoxaparin-treated baboons that are hemostatically compromised by aspirin. While our initial focus will be on the AXIMAB 14E11, an additional AXIMAB molecule, 1A6, which targets the apple 3 domain of FXI and prevents activation of FIX by FXIa, will also be evaluated as an alternative to 14E11. The AXIMAB approach represents a fundamentally new anticoagulation concept since clinical and experimental evidence suggests that blocking FXI activation by FXIIa will not produce side-effects that could limit effective dosing. Thus AXIMABs could represent a new antithrombotic strategy that is thrombus-specific and exceptionally safe. After successful completion of Phase I, the company will seek additional capital, either through Phase II or through private financing, to commence with the preclinical development program and advance AXIMAB into formal product development for acute thromboembolism indications. PUBLIC HEALTH RELEVANCE: Acute thrombotic blood vessel occlusion is a highly prevalent disorder with severe consequences, including death and chronic morbidity syndromes. While anticoagulant drugs (blood thinners) improve the outcome of diseases that are caused by blood clots, their usefulness is compromised by potentially severe bleeding- related (hemorrhagic) side-effects that restrict therapeutic dosing options. Accordingly, there remains an urgent unmet medical need for safer antithrombotic treatments. The proposed research addresses this need by evaluating a new product candidate, an antithrombotic antibody that targets a coagulation factor that contributes to blood vessel occlusion but is non-vital for normal blood coagulation necessary to arrest bleeding. Since the antibody is not expected to produce hemorrhagic side-effects, this approach could provide an effective yet safer alternative to currently marketed parenteral anticoagulants. 1